Mycobacteria infection induced cascade of epigenetic alterations promote training in bystander macrophages

Mycobacterium tuberculosis (Mtb) actively remodels host cell functions to promote its intracellular survival. Emerging evidence suggests that Mtb also significantly affects uninfected bystander cells within the host. However, the mechanisms underlying bystander cell modulation and their functional consequences during Mtb infection remain poorly understood. In this study, we show that Mtb infection alters the host epigenome, resulting in correlated gene expression changes not only in infected cells but also in bystander cells. We demonstrate that cytokines secreted by Mtb-infected cells, particularly interleukin-1 beta (IL-1β), mediate these epigenetic changes in bystander cells, creating an intracellular environment similar to that of infected cells. These epigenetic alterations in bystander cells lead to population-wide trained immunity, enhancing the response of both infected and bystander cells to subsequent secondary stimuli. Our findings provide a mechanism for the propagation of trained immunity in a cell population and highlight bystander cells as active participants in shaping the innate immune response to Mtb infection. Understanding these intercellular communications presents a new frontier for developing comprehensive strategies that target both infected and bystander cells to modulate the broader cellular and immune response to tuberculosis.